Latent-TGF-β has a domain swapped architecture.

The multifunctional cytokine TGF-β is a dimeric protein produced within a latent complex (L-TGF-β). Latency is maintained by disulfide linked homodimeric prodomains forming a ring encircling the non-covalently bound mature TGF-β homodimer. This configuration sterically inhibits mature TGF-β from binding to its receptors. For TGF-β to be activated and bind to its receptors it must either be released, or if not released, overcome steric hinderance within the latent complex. Integrin binding to L-TGF-β results in activation with or without release of TGF-β by deforming the ring through different yet incompletely understood mechanisms. The domain architecture of L-TGF-β, which is not clearly defined, is a gap in mechanistic understanding of L-TGF-β activation. Here we fill this critical gap-in-knowledge by definitive experimental evidence demonstrating a domain-swapped architecture of L-TGF-β.